Association of <i>SNCA</i> with Parkinson: Replication in the Harvard NeuroDiscovery Center Biomarker Study

Ding, Huangen; Sarokhan, Alison K.; Roderick, Sarah S.; Bakshi, Rachit; Maher, Nancy; Ashourian, Paymon; Kan, Caroline G.; Chang, Sunny Chun; Santarlasci, Andrea; Swords, Kyleen; Ravina, Bernard; Hayes, Michael T.; Sohur, U. Shivraj; Wills, Anne Marie; Flaherty, Alice W.; Unni, Vivek K.; Hung, Albert Y.; Selkoe, Dennis J.; Schwarzschild, Michael A.; Schlossmacher, Michael G.; Sudarsky, Lewis; Growdon, John H.; Ivinson, Adrian J.; Hyman, Bradley T.; Scherzer, Clemens R.

doi:10.1002/mds.23934

Cited by 24 publications

(19 citation statements)

References 7 publications

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“…The discovery (Satake et al 2009; Simon-Sanchez et al 2009) and subsequent validation (Pankratz et al 2009; Edwards et al 2010; Ding et al 2011; Mata et al 2011) of SNCA as a genetic risk factor for sporadic PD provided additional confirmation, with the PARK1/4 loci and Lewy body pathology, that this gene/protein is a key contributor to disease. Interestingly, MAPT , the gene that encodes the microtubule- associated protein tau (tau) was also identified and validated as a risk allele (Pankratz et al 2009; Simon-Sanchez et al 2009; Edwards et al 2010; Mata et al 2011; Rhodes et al 2011), although there appear to be ethnic differences (Satake et al 2009).…”

Section: 2 Etiologymentioning

confidence: 91%

Parkinson’s Disease

Mhyre¹,

Boyd²,

Hamill³

et al. 2012

Subcellular Biochemistry

347

203

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Parkinson’s disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800’s by James Parkinson as the ‘Shaking Palsy’. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.

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Section: 2 Etiologymentioning

confidence: 91%

Parkinson’s Disease

Mhyre¹,

Boyd²,

Hamill³

et al. 2012

Subcellular Biochemistry

347

203

View full text Add to dashboard Cite

show abstract

“…The analysis included two population‐based, incident cohort studies (Cambridgeshire Parkinson's Incidence from GP to Neurologist [CamPaIGN],17 Parkinsonism: Incidence, Cognition and Non‐motor heterogeneity in Cambridgeshire (PICNICS)14, 18; five purpose‐built biomarkers and clinical observational studies from academic centers (Harvard Biomarker Study [HBS],19, 20, 21, 22 PROfiling PARKinson's disease [PROPARK],16 and the French Drug Interaction with Genes in PD [DIGPD]); as well as two well‐phenotyped, failed phase III clinical trials with longitudinal, observational extension studies (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism [DATATOP]15; Parkinson Research Examination of CEP‐1347 Trial/A Longitudinal Follow‐up of the PRECEPT Study Cohort [PreCEPT/PostCEPT]13. Six cohorts enrolled patients with a diagnosis of PD established according to modified UK PD Society Brain Bank diagnostic criteria.…”

Section: Methodsmentioning

confidence: 99%

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Liu

Boot

Locascio

et al. 2016

Annals of Neurology

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236

240

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ObjectiveWe hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates.MethodsA total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.ResultsOverall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.InterpretationMutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685

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“…Diagnosis of cases and controls was assessed at each visit to ensure high diagnostic accuracy. Additional information about the participants enrolled in the HBS clinical trial was published previously (49) and can be found at www.neurodiscovery.harvard. edu/research/biomarkers.html.…”

Section: Methodsmentioning

confidence: 99%

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Networkbased metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were upand down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y followup period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.Parkinson's disease | HNF4A | PTBP1 | network analysis | blood biomarkers S ubstantial efforts have been devoted to the development of diagnostic strategies for Parkinson's disease (PD). In particular, changes in mRNA from cellular whole blood can facilitate the identification of dysregulated processes and diagnostic biomarkers for PD (1, 2). Several molecular signatures in blood have been identified. For example, 22 unique genes were found differentially expressed in blood of PD patients compared with healthy controls (1). Likewise, specific splice variants in blood were associated with PD in samples obtained from two independent clinical trials (2, 3). In addition, altered expression of the vitamin D receptor (VDR) in blood and reduced plasma levels of 25-hydroxy vitamin D 3 have been associated with PD (1, 4). Furthermore, plasma levels of the epidermal growth factor have been associated with cognitive decline in PD (5).Environmental stressors and genetic factors are most likely involved in the pathogenesis of PD. Among the genetic factors associated with PD, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal dominant PD (6) and a considerable risk factor in idiopathic forms of the disease (7,8). Given the complex interaction between environmental and genetic factors in sporadic PD, we integrated four independent microarray s...

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Association of SNCA with Parkinson: Replication in the Harvard NeuroDiscovery Center Biomarker Study

Cited by 24 publications

References 7 publications

Parkinson’s Disease

Parkinson’s Disease

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

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